Rat transcriptome biomarkers for the prediction of temporal lobe epilepsy

描述（由申请人提供）：癫痫持续状态（SE）是海马神经退行性变和突触重组的常见原因，最终可能或可能不会导致颞叶癫痫（TLE）的发展。虽然SE作为TLE的可能病因的作用已被认识到，但没有有效的预后工具可以可靠地预测SE后患者是否确实会发展为慢性癫痫。因此，尚不清楚SE后患者是否应该接受抗癫痫预防治疗，以及在哪种情况下，这种治疗的有效性难以评估。本提案的目的是利用基于微阵列的方法来分析颞叶癫痫大鼠模型血液中的表达变化，以确定TLE的新型和预后外周生物标志物。这将通过比较和鉴定实验动物外周血中常见的基因组变化来实现，无论动物品系、年龄、性别和SE模型如何。雄性和雌性Wistar和Sprague-Dawley大鼠在儿童期（出生后第35天）或成年期（出生后第90天）接受系统性匹罗卡品或海马体内kainic酸诱导的SE。在SE后1、3和7天采集的外周血样本将进行基因组分析。SE结束后，用脑电图和视频连续监测动物自发性复发性边缘癫痫发作的发生、频率和严重程度，持续6周。癫痫发作综合征将与血液基因组谱的变化进行回顾性分析。如果成功，我们的研究将允许对在TLE发展之前以特定方式改变表达的基因进行大规模平行，成本效益高的表达分析。该项目将生成定制的TLE预后生物标志物芯片，可用于筛查和诊断潜在的TLE患者，并前瞻性地评估抗癫痫治疗的有效性。

DESCRIPTION (provided by applicant): Status epilepticus (SE) is a common cause of hippocampal neurodegeneration and synaptic reorganization that ultimately may, or may not lead to the development of temporal lobe epilepsy (TLE). While the role of SE as a possible cause of TLE has been recognized, no effective prognostic tools exist that would reliably predict whether chronic epilepsy would indeed develop in post-SE patients. Hence it is not known whether post- SE patients should undergo antiepileptogenic preventive therapy, and in which case, the effectiveness of such therapy is difficult to assess. The goal of this proposal is to identify novel and prognostic peripheral biomarkers of TLE applying a microarray-based approach for the analysis of expression changes in the blood of rat models of temporal lobe epilepsy. This will be achieved through comparison and identification of genomic changes in peripheral blood of experimental animals that are common despite animal strain, age, sex, and SE model. Male and female Wistar and Sprague-Dawley rats will be subjected to SE induced by either systemic pilocarpine or intrahippocampal kainic acid during either childhood (postnatal day 35) or adulthood (postnatal day 90). Samples of peripheral blood collected one, three and seven days after SE, will undergo genomic assay. After SE, animals will be continuously monitored using both EEG and video for the occurrence, frequency and severity of spontaneous recurrent limbic seizures for a period of six weeks. Seizure syndrome will be retrospectively correlated with the changes in blood genomic profile. If successful, our study would allow a large-scale parallel, cost-effective expression analysis of genes whose expression is altered in a specific fashion prior to the development of TLE. The project will generate a custom TLE prognostic biomarker chip that can be used both to screen and diagnose potential TLE patients, and to prospectively evaluate the effectiveness of antiepileptogenic therapy. Project narrative: by either systemic pilocarpine or intrahippocampal kainic acid is an acute neurological condition that consists of an episode of long-lasting continuous seizure. After SE, significant portion of patients develop chronic epilepsy. Currently no diagnostic tools exist that would allow predicting whether post-SE patient would develop epilepsy. The current project proposes the development of a simple diagnostic blood test method that would allow predicting the development of epilepsy in post-SE patients. The test will be based on the detection of characteristic gene expression changes in the peripheral blood that precede the progression of epilepsy. This will provide an important diagnostic tool and could indicate the necessity of prophylactic treatment to prevent the development and progression of chronic epilepsy. Such a test would also be useful in prognostic assessment of the effectiveness of antiepileptic therapy.